Ischemia-reperfusion is a major cause of periventricular leukomalacia (PVL) in the premature infant. Developing cerebral WM is rendered vulnerable to hypoperfusion by the anatomic and functional integrity of the vascular supply. Pressure autoregulation, the principal system for intrinsic regulation of cerebral blood flow, is underdeveloped in the premature infant, and blood flow to WM is low. Common clinical factors, such as hypotension, hypoxemia, hypercarbia, and possibly cytokines may impair pressure autoregulation, predisposing to a pressure-passive cerebral circulation. Preliminary work by our group using continuous measurements of blood pressure and cerebral perfusion by near infrared spectroscopy has demonstrated impaired cerebrovascular autoregulation, i.e., a pressure-passive circulation, in certain premature infants and a strong correlation between this circulatory abnormality and the subsequent development of PVL and/or intraventricular hemorrhage. A central goal of the proposed research is to advance these studies by defining cerebral autoregulation in premature infants from the early hours of life through the first five postnatal days. Out long-term objectives are to understand the clinical factors that impair pressure autoregulation and thereby to identify reliable early predictors of imminent pressure-passive cerebral circulation, prior to the development of irreversible I/R injury, so that effective measures may ultimately be instituted to prevent the development of PVL. Specific Aim 1: To identify premature infants with impaired cerebrovascular autoregulation and especially a pressure-passive cerebral circulation. Specific Aim 2: To determine whether critical levels of hypercarbia, hypoxemia and hypotension are associated with a pressure-passive cerebral circulation. Specific Aim 3: To determine whether circulating levels of pro- inflammatory cytokines at birth and in the early newborn period are associated with a pressure-passive cerebral circulation. Specific Aim 4: To determine whether infants with a pressure-passive cerebral circulation subsequently develop PVL, both focal and diffuse components. Specific Aim 5: To determine the impact of focal and diffuse PVL in the newborn period on cerebral white matter development and on neurologic function at age one year.